Method and apparatus for preparing cytological specimens

ABSTRACT

An automated system for preparing a plurality of cytological specimens from a plurality of fluid samples in vials includes an apparatus for collecting a monolayer of cells from each sample and transferring the cells to a microscope slide for fixing, staining, and inspection. The system includes a first loading station for receiving the sample vials, a second loading station for receiving consumables such as filter membranes, a slide dispenser, and an unloading area for removing completed specimen slides. To maintain one-to-one correlation between the samples and specimens produced therefrom, the system includes a subsystem for identifying each sample and permanently marking each slide with corresponding indicia prior to transferring the specimen thereto.

RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/156,952 filed Sep. 18, 1998, entitled “SampleVial for Use in Preparing Cytological Specimen”, the disclosure of whichis herein incorporated by reference in its entirety. The presentinvention is also related to the invention disclosed and claimed in aU.S. patent application filed of even date herewith identified byAttorney Docket No. CYM-028 entitled “Method and Apparatus for PreparingCytological Specimens,” the disclosure of which is incorporated hereinby reference in its entirety.

TECHNICAL FIELD

[0002] The present invention relates to preparation of cytologicalspecimens and, more specifically, to an automated method and apparatusfor preparing a plurality of cytological specimens from a common numberof patient samples and maintaining one-to-one correlation between thepatient samples and the specimens.

BACKGROUND

[0003] Cytology is a branch of biology dealing with the study of theformation, structure, and function of cells. As applied in a laboratorysetting, cytologists, cytotechnologists, and other medical professionalsmake medical diagnoses of a patient's condition based on visualexamination of a specimen of the patient's cells. A typical cytologicaltechnique is a “pap smear” test, in which cells are scraped from awoman's cervix and analyzed in order to detect the presence of abnormalcells, a precursor to the onset of cervical cancer. Cytologicaltechniques are also used to detect abnormal cells and disease in otherparts of the human body.

[0004] Cytological techniques are widely employed because collection ofcell samples for analysis is generally less invasive than traditionalsurgical pathological procedures such as biopsies, whereby a tissuespecimen is excised from the patient using specialized biopsy needleshaving spring loaded translatable stylets, fixed cannulae, and the like.Cell samples may be obtained from the patient by a variety of techniquesincluding, for example, by scraping or swabbing an area, or by using aneedle to aspirate body fluids from the chest cavity, bladder, spinalcanal, or other appropriate area. The cell samples are placed insolution and subsequently collected and transferred to a glass slide forviewing under magnification. Fixative and staining solutions may beapplied to the cells on the glass slide for preserving the specimen forarchival purposes and for facilitating examination.

[0005] It is generally desirable that the cells on the slide have aproper spatial distribution, so that individual cells can be examined. Asingle layer of cells is typically preferred. Accordingly, preparing aspecimen from a fluid sample containing many cells typically requiresthat the cells first be separated from each other by mechanicaldispersion, fluidic shear, or other techniques so that a thin, monolayerof cells can be collected and deposited on the slide. In this manner,the cytotechnologist can more readily discern abnormal cells. The cellsare also able to be counted to ensure that an adequate number of cellshave been evaluated.

[0006] Certain methods and apparatus for generating a thin monolayer ofcells on a slide advantageous for visual examination are disclosed inU.S. Pat. No. 5,143,627 issued to Lapidus et al. and entitled “Methodand Apparatus for Preparing Cells for Examination;” U.S. Pat. No.5,240,606 issued to Lapidus et al. and entitled “Apparatus for PreparingCells for Examination;” U.S. Pat. No. 5,269,918 issued to Lapidus et al.and entitled “Clinical Cartridge Apparatus;” and U.S. Pat. No. 5,282,978issued to Polk, Jr. et al. and entitled “Specimen Processor Method andApparatus,” all of which are assigned to the assignee of the presentinvention and all of the disclosures of which are incorporated herein byreference in their entirety.

[0007] According to one method disclosed in these patents, a patient'scells in a preservative fluid in a sample container are dispersed usinga spinning sample collector disposed therein. A controlled vacuum isapplied to the sample collector to draw the fluid through a screenfilter thereof until a desired quantity and spatial distribution ofcells is collected against the filter. Thereafter, the sample collectoris removed from the sample container and the filter portion impressedagainst a glass slide to transfer the collected cells to the slide insubstantially the same spatial distribution as collected.

[0008] While apparatus manufactured according to the teachings of one ormore of these patents have been commercially successful, such as theThinPrep® 2000 System manufactured and sold by Cytyc Corporation locatedin Boxborough, Mass., such apparatus requires substantially constantattendance by a trained operator. For example, for each specimen to beprepared, the operator must load the system with an open sample vialcontaining the patient's cells in preservative fluid, a sample collectorwith filter, a glass slide, and an open fixative bath vial containing afixative solution. The system then cycles automatically, the cells beingdispersed by the sample collector, collected against the filter, andtransferred to the slide. The slide is then automatically deposited inthe fixative bath vial where it must be retrieved by the operator formanual loading in a staining rack for further processing. Thereafter,the sample vial and sample collector must be removed from the system, toavoid inter-sample contamination, before replacements and a new slideare installed to produce another specimen from a different patient'ssample.

[0009] Once a specimen is prepared, fixed, and stained, the specimen maybe manually visually inspected by a cytotechnologist, typically undermagnification, and with or without various sources of illumination.Alternatively or additionally, automated machine vision systems havebeen adapted to aid cytological inspection. For example, an automatedvision system may perform a preliminary assessment of the entire slideon which the specimen is disposed to alert the cytotechnologist topotentially the most relevant areas of the slide for close inspection,or may be used to rescreen specimens already analyzed by thecytotechnologist.

SUMMARY OF THE INVENTION

[0010] While automated specimen preparation systems such as thosedescribed hereinabove perform as designed, it is desirable to furtherreduce manual intervention required of a system operator so as toincrease system throughput and operating efficiency. Accordingly, it isdesirable to provide the capability wherein a plurality of sample vials,sample collectors with filters, and inspection media such as, forexample, glass slides may be loaded in the system. The system thencycles automatically until all of the sample vials are processed andrespective specimen slides produced. As a result, after initial loading,the system can operate unattended.

[0011] In one embodiment of the invention, a system includes a samplevial tray for loading of a plurality of closed, capped sample vials. Thevials include particles of interest, such as cells, tissue samples,assay product, or other material, typically dispersed in a fluid medium.A sample vial transfer assembly serially retrieves each sample vial,unscrewing a cap thereof, and positioning the now open vial in aposition for cooperation with a sample collector and filter, which maybe drawn automatically from another tray having a plurality of samplecollectors. A sample collector or other mechanism prepares the samplefor collection such as, for example, by agitating the sample in a mannerso as to create a generally uniform dispersion of particles of interestthroughout the sample. Once the particles cells are dispersed, collectedagainst the filter, and transferred to a slide drawn automatically froma slide dispenser having a plurality of clean slides stored therein, theslide is then automatically deposited in a fixative bath vial for aperiod sufficient to fix the specimen on the slide. Alternatively, thefixative solution may be applied directly to the specimen on the slideby spraying with an air brush or similar technique. In either case, theslide may then be transferred to one of a number of multi-positionstaining racks previously loaded in the system, so that the fixativesolution may dry. Once a first patient's specimen is prepared, the opensample vial is recapped and replaced in the sample vial tray. The filterof the sample collector may be breached to prevent reuse and resultantinter-sample contamination. The next sample vial can then be retrievedand the specimen preparation method repeated until all of the samplevials are processed. Accordingly, once the system operator loads thesample vial tray, sample collector tray, slide dispenser, and stainingracks, and initiates the automatic sequence, the system can operateunattended.

[0012] In order to maintain the integrity of the specimens so produced,it is desirable to maintain one-to-one correlation between the contentsof the sample vials and the respective specimens produced therefrom.When a cell sample is collected from a patient and deposited in thepreservative fluid in the sample vial, creating cellular particles in aliquid suspension, the vial may be marked with unique identifyingindicia corresponding to the type of sample, patient, date obtained,etc. In one embodiment, the identifying indicia may be a bar code label.When the sample vial is loaded into the system and retrieved from thesample vial tray by the sample vial transfer assembly, the indiciacorresponding to the sample is identified. In the case of a bar code, alaser bar code scanner can be used.

[0013] Next, an analytical element, such as a microscope slide, ismarked with indicia corresponding to the sample indicia. In oneembodiment, the analytical element is marked with ink transferredthereto by a printer. The ink may be transferred to multiple overlappinglocations, spatially offset from each other on the analytical element,to improve the readability of the element indicia.

[0014] The element indicia are then read automatically by the system. Inthe case where the element indicia are man-readable alphanumericcharacters, an optical character recognition system can be employed inthe reading step. Once the system verifies that the element indiciacorresponds to the sample indicia, the cells in the sample vial aredispersed, collected, and transferred to the analytical element toproduce the specimen. In one embodiment, the system collects a spatialdistribution of the cellular particles from the liquid suspension anddisposes the collected particles on a stratum of the analytical elementor slide. The spatial distribution may be substantially a monolayer ofcells collected on a filter or porous membrane of a sample collector.The filter or membrane of the sample collector may be breachedmechanically, pneumatically, hydraulically, or otherwise in order toprevent reuse of the sample collector and resultant inter-samplecontamination.

[0015] An apparatus according to the invention for processing a specimenfrom a fluid sample may include a processor, an identifier incommunication with the processor for identifying indicia correspondingto the sample, a marker in communication with the processor for markingan analytical element with indicia corresponding to the sample indicia,and a reader in communication with the processor for reading the elementindicia. Once the processor verifies that the element indiciacorresponds to the sample indicia, a specimen transferrer incommunication with the processor transfers a specimen from the sample tothe analytical element.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The invention, in accordance with preferred and exemplaryembodiments, together with further advantages thereof, is moreparticularly described in the following detailed description taken inconjunction with the accompanying drawings in which:

[0017]FIG. 1 is schematic front view of an automated specimen processingapparatus in accordance with one embodiment of the present invention;

[0018]FIG. 2 is a schematic top plan view of the specimen processingapparatus depicted in FIG. 1;

[0019]FIG. 3 is a schematic front view of an identification correlationsubsystem of a specimen processing apparatus in accordance with oneembodiment of the present invention;

[0020]FIG. 4 is a schematic top plan view of the identificationcorrelation subsystem of a specimen processing apparatus depicted inFIG. 3;

[0021]FIG. 5 is a schematic perspective view of a capped sample vial inaccordance with one embodiment of the present invention;

[0022]FIG. 6 is a schematic perspective view of a sample collectorduring cell collection in accordance with one embodiment of the presentinvention;

[0023]FIG. 7A is a schematic side view of a pre-contact condition of asample collector approaching a specimen slide;

[0024]FIG. 7B is a partial schematic cross-sectional view of theapparatus depicted in FIG. 7A taken along line 7B-7B.

[0025]FIG. 7C is a schematic side view of an initial contact conditionfor a sample collector contacting a specimen slide;

[0026]FIG. 7D is a schematic side view of a full contact condition of asample collector contacting a specimen slide;

[0027]FIG. 8 is a schematic perspective view of a rotatable interfacefor mating with a torque pattern of a sample vial cap;

[0028]FIG. 9A is a schematic perspective view of a unidirectionalinterface in a sample vial tray for mating with anti-rotation featuresof a sample vial body; and

[0029]FIG. 9B is a schematic perspective view of a bi-directionalinterface for mating with anti-rotation features of a sample vial body.

DESCRIPTION

[0030]FIGS. 1 and 2 are schematic front and top plan views of anautomated specimen preparing system 10 for preparing a plurality ofspecimens from a plurality of fluid samples. The system 10 may bemounted on a wheeled instrument cart 12 for portability. Depicted withan upper cover 14 and front door 16 in open positions, the system 10includes a specimen preparing apparatus 18 or transferrer, functionallyof the type disclosed in the aforementioned patents subject toimprovements discussed further hereinbelow. Namely, the specimenpreparing apparatus 18 includes subassemblies for automaticallydispersing, collecting, and transferring a monolayer of cells to ananalytical element, such as a microscope slide. The particularstructural details of the specimen preparing apparatus 18, however, mayvary from those disclosed in the aforementioned patents.

[0031] The system 10 includes a first loading station 20 for receiving aplurality of patient samples, each disposed in a sample vial 22, as bestseen in FIG. 5. As depicted, the sample vial loading station 20 may havemore than one tier to accommodate multiple sample vial trays 24, twotrays 24 being shown. Each tray 24 is removable to facilitate handlingand preloading of the vials 22. In one embodiment, each tray 24 mayinclude locations for forty samples vials 22, providing a system 10 thatcan automatically process up to eighty samples without operatorintervention. For a system 10 with a process cycle time of about ninetyseconds per sample, eighty samples can be processed in about two hoursof continuous, unattended operation.

[0032] The system 10 also includes a second loading station 26 forreceiving a plurality of sample collectors 28 disposed in a samplecollector tray 30. As best seen in FIG. 6, each sample collector 28 hasa porous membrane or filter 29 at one end thereof against which cellsare collected. The sample collector loading station 26 may have morethan one tier to accommodate multiple sample collector trays 30, twotrays 30 being shown. Each tray 30 is removable to facilitate handlingand preloading of the sample collectors 28. In one embodiment, each tray20 may include locations for one hundred sample collectors 28, providinga system 10 which can automatically process the eighty samples withoutoperator intervention. The collectors 28 may also be provided to theoperator preloaded in the collector tray 30, which may be reusable ordiscardable, as desired. Both loading stations 20, 26 include elevatorsfor raising and lowering the trays 24, 20, as required, so that samplevial and collector transfer assemblies can access, respectively, each ofthe sample vials 22 and collectors 28.

[0033] Blank glass microscope slides are preloaded in two removablecartridges 32, each with the capacity to hold one hundred slides. Twocartridges 32 are provided to ensure that there are a sufficient numberof slides available in the system 10 to process the maximum number ofsample vials 22. While glass microscope slides are typically used forpreparing cytological specimens, other analytical elements, such asnatural or synthetic material assay strips and the like, are suitablefor other analyses and testing, as known by those skilled in the art,and could be employed in the system 10 with suitable handling equipment.

[0034] One or more staining racks 34 may be provided in an unloadingarea 36 of the system 10 to receive the slides once the cytologicalspecimens have been transferred thereto. In the depicted embodiment,four staining racks 34 are provided, each with a capacity of twentyslides. Accordingly, eighty sample vials 22 can be processed withouthaving to remove the staining racks 34. Staining rack adaptors may beprovided so that the staining racks 34 can be loaded into automated,commercially available cytological specimen stainers after removal fromthe system 10. Accordingly, prepared specimens can be efficiently andrapidly unloaded from the system 10 and the specimens stained withminimal manual intervention.

[0035] Once a specimen has been transferred to a slide and before theslide is disposed in the staining rack 34, a fixitive solution may beapplied to the specimen at a coating station 38. The coating station 38includes a fixitive reservoir 40 which holds the solution used to fix orpreserve the specimen on the slide after preparation by the system 10.In one embodiment, the reservoir has sufficient capacity to allow atleast a day and preferably a week of average usage without the need forrefilling or replacement. The fixitive may be applied to the specimen byan air brush technique in which the fixitive solution is gently sprayedon the specimen so as not to disturb the spatial distribution of thecells on the slide.

[0036] More specifically, in one embodiment, an airbrush having agenerally conical spray distribution pattern may be used to apply asubstantially uniformly dense layer of fixitive solution to a generallycircular cell transfer area on the slide. A fine mist may be applied inone or more short duration bursts to prevent displacing a monolayer ofcells on the slide, typically using a very small volume of fluiddispensed from the airbrush using very low differential air pressure.For example, each burst may apply about 20±2 μl of fixitive solutionover a period of about 0.6 seconds. A slight positive pressure may bemaintained in the reservoir 40 to compensate for any pressure head,thereby maintaining control of the dispensed volume per burst. Theairbrush may be of any conventional design capable of handling the smallvolumes applied and capable of providing the desired uniform conicalspray distribution pattern. In general, primarily an airbrush nozzle,needle valve, and body are employed, with flow being controlled by anexternal valve, rather than a trigger valve typically supplied with theairbrush. The pressure source applied to the airbrush may be calibratedand maintained at a fixed pressure in order to ensure a predeterminedfixative flow rate for a particular airbrush, thereby achieving thedesired dispensed volume per burst.

[0037] During preparation of each specimen, a small volume ofpreservative fluid from the sample vial 22 is drawn through thecollector membrane 29. A waste bottle 42 is provided in fluidiccommunication with the specimen preparing apparatus 18 so that wastefluid can be drained during specimen preparation. The waste bottle 42may be mounted to an interior of the front door 16 to facilitate removaland replacement of the bottle 42 for emptying.

[0038] A waste bin 44 may also be provided to catch used samplecollectors 28. Prior to being discarded, the porous membrane or filter29 of each collector 28 may be breached so that the collector 28 cannotbe reused and possibly contaminate another specimen. The membrane 29 maybe breached by any of a variety of methods. For example, the collector28 may be overpressurized, pneumatically with air or hydraulically withfluid, so as to burst the membrane. Alternatively, the membrane 29 canbe mechanically ruptured, for example, by impressing the membrane 29 ona sharp object, such as a pointed protrusion or knife edge mounted inthe system 10. For preparing cytological specimens, the membrane mayhave a pore size on the order of about ten microns or less.

[0039] A computer controller or processor 46 is provided to communicatewith and coordinate operation of the various sensors and components ofthe system 10 to permit automatic, unattended operation during specimenpreparation. The processor 46 includes an appropriate operator interface47 with associated input keypad or buttons and an output display, suchas a liquid crystal diode display. Instructions, prompts, and errormessages may be in text, error code, or symbol formats. Text displaysmay be in a variety of operator selectable languages, such as English,French, German, Italian, Japanese, and Spanish. Audible outputscorresponding to operator prompts, error conditions, keypad inputs, andcompletion of automatic processing may be provided. A thermal paperprinter 48 or other type of printer may be provided, as well, togenerate a permanent paper record of system operation and sampleprocessing. For example, for each batch of eighty or fewer sample vials22 processed, the printer 48 may generate a report containing the dateand time processing began, a listing of the sample vials 22 notsuccessfully processed (including error type and tray location), and alisting of the sample vials 22 successfully processed (including sampleidentification information and tray location).

[0040] In order that the system 10 maintains correlation between eachsample vial 22 and a respective specimen prepared therefrom, anidentification correlation subsystem 50 is provided, as depictedschematically in front and top plan views in FIGS. 3 and 4,respectively. In accordance with one embodiment of the presentinvention, in order to prepare a specimen from a sample vial 22, aselected capped vial 22 a is removed from one of the sample vial trays24 by a sample vial transfer assembly 52. The vial transfer assembly 52includes a four-fingered gripper 54 configured to reliably andrepeatable grasp a cap 56 of the vial 22 a. The vial transfer assembly52 is movable about a plane above the vial tray 24, left to right andinto and out of the drawing as depicted in FIG. 3, so that the gripper54 can be aligned above any of the forty vials 22 loaded in the tray 24.Once aligned with a desired vial 22 a, the tray 24 is raised by the trayelevator, the vial cap 56 grasped by the gripper 54 and tightened aswill be discussed in greater detail hereinbelow, and the tray 24lowered. In order to access vials 22 on the other tray 24, the vialtransfer assembly 52 can be retracted to one side, outside a footprintof the trays 24 and the tray elevator operated to raise or lower thetray 24, as necessary. Similar handling is provided for the samplecollectors 28 and collector trays 30.

[0041] Each vial 22 includes identifying indicia, such as a bar codelabel 58 mounted thereon, which corresponds to and uniquely identifiesthe vial 22 and the sample contained therein. The selected vial 22 a isthen presented by the vial transfer assembly 52 to an identifier, suchas a laser scanner bar code reader 60, so that the particular vial 22 acan be identified. Because the circumferential orientation of the vials22 in each tray 24 and that of the respective bar code labels 58 canvary, upon presentation to the bar code reader 60, the vial transferassembly 52 rotates the sample vial 22 a about a vertical axis passinggenerally through an axial centerline thereof, as best seen in FIG. 4,to present the label 58 to the reader 60.

[0042] Once the bar code label 58 or other identifying indicia has beenidentified and communicated to the processor 46, the processor 46directs the preparation of an analytical element, such as a microscopeslide 62, for receipt of a specimen from the selected vial 22 a.

[0043] Referring to FIG. 4, a slide carriage 64, translatable along acarriage rail 66, first extracts a slide 62 from one of the slidecartridges 32. Each slide 62 has tightly toleranced dimensions andchamfered edges to facilitate handling and transfer of the slide 62 bythe components of the system 10 and minimize the likelihood ofmishandling or jamming. In one embodiment, the slide 62 is manufacturedfrom glass and has a width of about one inch, a length of about threeinches, and a thickness of about 0.04 inches. One end 68 of the slide 62is frosted or coated to facilitate marking, as will be discussed ingreater detail hereinbelow. The frosted end 68 may have an area of aboutone square inch. A frosted annulus 70, defining an area to where thecells are transferred, may also be provided to facilitate manual orautomatic scanning of sparse specimens. The bounded specimen area mayhave an area of about one square inch, substantially equivalent to thesurface area of the membrane 29. Additionally, one corner 72 of thefrosted end 68 of each slide 62 may be chamfered to a greater degreethan the other corners to ensure proper orientation of the slide 62 inthe slide cartridge 32 and proper presentation of the slide 62 todownstream components.

[0044] Once the bar code label 58 on the sample vial 22 a has beenidentified and before the sample vial 22 a is uncapped and a specimenproduced therefrom, the slide carriage 64 conveys the slide 62 to amarker in communication with the processor 46 for marking the slide 62with indicia corresponding to the sample indicia on the bar code label58. In one embodiment, the marker may be a printer 74, such as an inkjet printer, thermal printer, laser printer, or other suitable markercapable of producing substantially permanent indicia on the slide 62. Inthe depicted embodiment, the printer 74 is a dot matrix impact printerutilizing a multi-pin impact head 76 and replaceable ribbon cartridge78, which feeds an ink ribbon 80 to a zone between the impact head 76and the slide 62.

[0045] The processor 46 next directs the printer 74 to mark the slide62. The slide indicia may have any of a variety of forms including oneor more alphanumeric characters, as shown generally at 82. It isgenerally desirable to mark the slides 62 with man-readable indicia sothat the cytologist examining a fixed, stained specimen can readilyidentify the specimen and associated sample from which the specimen wasprepared. Further, specimens are often archived and retained forextended periods. Accordingly, it is generally desirable to avoid usingan indicia standard that may fall into disuse or become obsolete. Whilethe slide indicia may be marked on an adhesive label bonded to the slide62, subsequent processing such as fixing and staining may degrade theindicia or bond. Because specimen slides 62 are often archived in slidefile drawers, it is generally desirable that the slide indicia 82 beoriented along the width or narrow dimension of the frosted end 68 so asto be readable without requiring removal of the slide 62 from the filedrawer.

[0046] The slide indicia printing method and printing media should beresistant to the solvents used in the specimen preparing, fixing, andstaining processes. Typical solvents include ethanol, methanol, xylene,water, and a clarifier solution consisting of 0.025% glacial acetic acidin distilled water. In general, commercially available carbon blackbased printing ink ribbons 80 have been found to perform well whenprinting on frosted ends 68 produced by coating the ends of the slides62 with a white epoxy paint material.

[0047] In order to generate readily discernible characters 82 using alow cost printer 74, the processor 46 may control operation of theprinter 74 and the slide carriage 64 so as to first transfer a spot ofink to a first location on the slide 62 and then transfer another spotof ink to a second location offset spatially and slightly overlappingthe first location. By double-striking, or alternatively striking athird or more times in different offset directions to blend the inkspots in a particular region of the character, a relatively low costnine pin dot matrix printer can produce alphanumeric characterssubstantially visually consistent with those produced by a much moreexpensive dot matrix printer having many more pins in the impact head.

[0048] Once the slide 62 is marked, the processor 46 directs the slidecarriage 64 to advance the slide 62 along the carriage rail 66 to areader in communication with the processor 46 for reading the slideindicia 82. In the case where the specimen indicia is composed ofalphanumeric characters, the reader may be an optical characterrecognition (OCR) scanner 84 or system. In one embodiment, a total offour strikes are employed per pin using a nine pin printer in order tomeet OCR font specifications typical for higher resolution dot matrixprinters.

[0049] The processor 46 verifies both that the slide indicia 82 isreadable by the OCR scanner 84 and that the slide indicia 82 correspondsto the sample indicia identified from the bar code label 58 on theselected vial 22 a. In the event the slide indicia 82 cannot be read orthe slide indicia 82 does not correspond to the sample indicia, theslide 62 may be removed automatically from the slide carriage 64 usingan ejector or other apparatus, as discussed in greater detailhereinbelow, and discarded in the waste bin 44 or other waste receivingarea. If multiple slides 62 fail in succession or if more than apredetermined number of slides fail during processing of a batch ofsample vials 22, the system 10 may be programmed optionally to haltautomatic operation and alert the operator with a suitable errormessage.

[0050] Upon verification of both criteria, the sample vial transferassembly 52 removes the cap 56 from the sample vial 22 a so that thespecimen preparing apparatus 18 can cycle. A sample collector 28 istaken automatically from the collector tray 30 at the second loadingstation 26 and inserted into the specimen preparing apparatus 18.Thereafter, the membrane 29 of the collector 28 is inserted into thespecimen vial 22 a to a predetermined depth as shown in FIG. 6 and, inone embodiment, the collector 28 is rotated to disperse the cells in thepreservative fluid. A vacuum system 88 applies a controlled pressure andvacuum cycle to the collector 28 so that cells are collected in amonolayer against the membrane 29. The cells are subsequentlytransferred to the zone within the frosted annulus 70 on the slide 62 asshown schematically in FIGS. 7A-C. According to another embodiment, thesample vial 22 may be rotated prior to uncapping to disperse the cellsin the preservative solution, as will be discussed in greater detailhereinbelow.

[0051] In order to provide for transfer of the collected cells to theslide 62 without disturbing the spatial distribution thereof, it isdesirable that the membrane 29 of the collector 28 first contact theslide 62 generally at a single location, forming a predetermined smallpre-contact angle between the substantially planar membrane 29 and adeposition surface of the slide 62, and then gently and gradually enterinto complete contact with the slide 62.

[0052] As depicted in FIG. 7A, after collecting the cells on themembrane 29, the specimen preparing apparatus 18 inverts the collector28 to drain any excess fluid therein into the waste bottle 42 mounted onthe cart door 16. The apparatus 18 slowly elevates the membrane 29 to aposition proximate the slide 62, which is retained in an invertedorientation in a slide holder 90 hanging from two studs 92 captured bythe slide carriage 64. Insofar as the studs 92 are of different lengths,the holder 90 and the slide 62 are positioned in an orientation which isslightly offset from horizontal.

[0053]FIG. 7B is a partial schematic cross-sectional view of thespecimen preparing apparatus 18 and slide holder 90 depicted in FIG. 7A,taken along line 7B-7B. Viewed in conjunction with FIG. 7A, as theapparatus 18 continues to elevate the collector 28, two pre-adjustedjack screws 94 first contact the slide holder 90 at one end thereof. Asthe apparatus 18 elevates the collector 28 further, the holder 90achieves a more horizontal orientation due to contact with the jackscrews 94 until an edge of the membrane 29, shown generally at 29 a inFIG. 7C, contacts the slide 62. At this point in the cycle, the angleformed between the membrane 29 and the slide 62 may be on the order ofseveral degrees or less, typically 0.75±0.25 degrees.

[0054] As the apparatus 18 is raised further to an end-of-travelposition, as depicted in FIG. 7D, substantially full planar contactresults between the membrane 29 and the slide 62, as the slide holder 90is effectively fully supported by the membrane end of the collector 28.Note the clearance between the jack screws 94 and the holder 90 at theend-of-travel position. Accordingly, by initially providing a two pointcontact between the jack screws 94 and slide holder 90, the holder 90and, as a result, the slide 62 mounted thereon, can be oriented in sucha manner as to be nearly parallel to the collector membrane 29 when themembrane edge 29 a first touches the slide 62. As the apparatus 18 movesto the end-of-travel position, the slight rotation of the holder 90through about one degree or so conforms the membrane 29 to the surfaceof the slide 62, gently displacing any excess liquid from the surface ofthe membrane and substantially preventing the capture of air bubblesbetween the membrane 29 and the slide 62 without disturbing the spatialdistribution of the cells. With intimate contact now achieved betweenthe membrane 29 and the slide 62, the cells captured therebetween can bereadily transferred, for example with minimal positive pressurization ofthe collector 28 which slightly bows the membrane into a convexconfiguration.

[0055] As the membrane 29 is thereafter withdrawn from the surface ofthe slide 62, the reverse procedure takes place, leaving the transferredcells on the slide 62 in a undisturbed monolayer, substantially similarto the spatial distribution created when initially collected against themembrane 29. By providing clearance between the studs 92 and the slideholder 92 which affords a limited vertical range of motion of the slideholder 90, monolayers of cells can be reliable and repeatablytransferred to slides 62 from a plurality of patient samples.Additionally, because the slide holder 90 is effectively floating at thetime of cell transfer on a fluid bearing created at the interface of themembrane 29 and the slide 62, variability in slide thickness, membranelocation, and slide/membrane parallelism are readily accommodated.Accordingly, there is no requirement for time consuming, precision setupof the apparatus 18 and slide holder 90 to ensure proper cell transfer.

[0056] After transferring the cells to the slide 62, a fixitive solutionmay then be applied to the transferred specimen and the slide 62transferred from the slide carriage 64 to one of the staining racks 34at the unloading area 36 using a slide transfer assembly such as atranslating slide ejector 86. The slide ejector 86 and/or the unloadingarea 36 may include automatic height and side-to-side translationcapability, so as to be able to accept the prepared specimen slide 62 ina next open slot in any one of the plurality of staining racks 34.

[0057] After preparation of the specimen, the membrane 29 of the usedcollector 28 is breached and the collector 28 discarded in the waste bin44. The cap 56 is replaced on the sample vial 22 a and the vial 22 areturned to its location in the vial tray 24. If there exist additionalsample vials 22 which have not yet been processed, a next vial 22 isremoved automatically, the sample indicia identified, and a nextspecimen prepared therefrom according to the steps describedhereinabove.

[0058] In order that the system can process automatically the specimensfrom fluid samples in the sample vials 22, each vial 22 and cap 56includes one or more structural features which facilitate grasping ofthe closed, capped vial 22 by the sample vial transfer assembly 52, aswell as removal and reinstallation of the cap 56. In one embodimentdepicted in FIG. 5, the sample vial 22 includes a body 23 having agenerally cylindrical outer surface, an open end, a closed end, and atleast one lug 25 disposed about the outer surface. The lug 25 performsan anti-rotation function, preventing the body 23 from rotating whendisposed against adjacent structure. The sample vial cap 56 isreleasably engagable with the body 23, the cap 56 including an outersurface with a torque pattern 27 thereon for mating with a rotatableinterface of the sample vial transfer assembly 52 as discussed morefully hereinbelow. A seal is disposed between the body 23 and the cap 56so as to be capable of forming a substantially fluid-tight sealtherebetween.

[0059] Instead of a single anti-rotation lug 25, the body 23 may includea plurality of lugs 25 disposed about a perimeter of the body 23, suchas the six equi-spaced lugs 25 of the embodiment of FIG. 5. While thelugs 25 may be disposed anywhere on the body 23 accessible to the samplevial transfer assembly 52 or related structure of the system 10, thelugs 25 may be disposed advantageously proximate the open end of thebody 23 and the cap 56. In this manner, torque may be applied to boththe body 23 and the cap 56 at approximately the same axial plane tominimize any induced moment in the vial 22 during removal andinstallation of the cap 56.

[0060] The sample vial body 23 may be manufactured from a substantiallytransparent or translucent material so that a level of the fluid sampletherein can be readily discerned by the system operator to ensure thepresence of a sufficient amount of fluid for subsequent processing. Thebody 23 may also include fluid level indicia 31 disposed on the outersurface thereof, such as a circumferentially-disposed frosted annularband. Accordingly, the vials 22 can be rapidly visually screened by theoperator prior to loading in the vial tray 24 to prevent loading a vial22 with too much or too little fluid which might not be processedsuccessfully by the specimen preparing apparatus 18. The fluid levelindicia 31 may be provided in addition to the sample bar code label 58discussed hereinabove.

[0061] The cap may be manufactured from polypropylene or other suitablematerial and may include knurling 33 or other anti-slip feature along anouter perimeter thereof to facilitate manual handling by a nurse ordoctor during sample procurement, as well as the system operator duringmanual loading and loading of the sample vial trays 24. The cap torquepattern 27 may be at least one generally radially disposed rib 35. Inthe embodiment depicted in FIG. 5, the torque pattern 27 includes sixgenerally radially disposed, equi-spaced ribs 35.

[0062] The seal may be manufactured from any suitable material which canbe sterilized and which is capable of withstanding attack by thepreservative fluid, which may typically contain a solution of methanolin a buffer. For example, the seal may be manufactured from amulticomposite material such as a resilient rubber layer laminated witha suitable vapor barrier and may be disposed within the cap 56. The cap56 and the body 23 may have mating screw threads, a bayonet fitting, orother retention feature so as to be releasably engageable. In oneembodiment, a substantially fluid-tight seal between the body 23 and thecap 56 may be formed when at least between about 5 and 50 inch-pounds oftorque is applied to the cap 56 relative to the body 23. A more typicaltorque range may be on the order of about 20 to 30 inch-pounds, withabout 25 inch-pounds being preferred. To ensure that the fluid-tightseal is produced when the patient's cells are first disposed in thepreservative fluid and to prevent leakage or evaporation of thepreservative fluid during transport and storage, each of the cap 56 andthe body 23 may include alignment markers 37, 39, such that thealignment markers 37, 39 indicate a fluid-tight seal when at leastaligned.

[0063]FIG. 8 is a schematic perspective view of one design of arotatable interface 142 disposed radially inwardly of the grippers 54 ofthe vial transfer assembly 52. The interface 142 includes a torquepattern 144 for mating with the torque pattern 127 of the sample vialcap 56. The rotatable interface 142 is shown inverted, to better depictthe interface torque pattern 144 formed therein. In this embodiment, theinterface torque pattern 144 includes six raised wedge-shaped sectors146. The sectors 146 are substantially equi-spaced about the interface142, which is rotatable about a longitudinal axis 148 thereof, and sizedto mate with the torque pattern 127 of the cap 56. Accordingly, the ribs35 of the cap 56 fit in grooves 150 formed between the sectors 146 ofthe interface 142 and react against substantially vertical faces of thesectors 146 to permit both loosening and tightening of the cap 56.

[0064] To prevent rotation of the sample vial body 23 during theseoperations, the body 23 may be disposed in a bore 152 formed in thesample vial tray 24 having a unidirectional interface 154 along an edge160 thereof for mating with the lugs 18 of the body 23, as depicted inFIG. 9A. The interface 154 includes six ramps 156, each including asubstantially vertical face 158 which abuts one of the body lugs 25.Accordingly, the capped vial 22 may be disposed in the bore 152 with aflange 140 of the body 23 supported along the edge 160. The rotatableinterface 142 may then be engaged with and tighten the cap 56, to ensurea fluid-tight seal prior to removing the vial 22 from the sample tray24. Due to the orientation of the ramps 156, the lugs 25 react againstthe ramp faces 158 during tightening to positively secure and preventrotation of the vial body 23.

[0065] Once the cap 56 has been tightened, the vial transfer assembly 52may grasp the capped vial 22 about the circumference of the cap 56 withthe grippers 54, remove the vial 22 from the bore 152 in the tray 24,rotate the vial 22 in front of the bar code reader 60, and deposit thecapped vial 22 in a bore 162 formed in a vial sleeve 164, such as thatdepicted in FIG. 9B in wire form representation. The six lugs 25 of thecapped vial 22 are received in every other one of twelve axiallyextending slots 166 formed along an upper edge 168 of the sleeve 164,the flange 140 of the vial 22 being supported by the edge 168. Once inthe bore 162 with the lugs 25 disposed in the slots 166, furtherprocessing may proceed.

[0066] As discussed hereinabove, a slide 62 is printed and the slideindicia 82 verified as being readable and corresponding to the vial barcode label 58. The vial 22 may then be uncapped and the sample collector28 can be disposed in the vial 22 and rotated to disperse the cells inthe sample. According to an alternative embodiment, once the capped vial22 is disposed in the sleeve 164 and before the vial 22 is uncapped, thesleeve 164 may be rotated in one or both directions to disperse thecells in the preservative solution. Thereafter, a pin, clamp, or otherstructural feature of the system 10 may engage one of a series ofnotches 170 formed in a flange 172 of the sleeve 164 to prevent rotationof the sleeve 164 and the vial 22 disposed therein while the rotatableinterface 142 engages and unscrews the cap 56. The cap 56 is thenretracted by the gripper 54 of the vial transfer assembly 52 and thesample collector 28 disposed in the preservative solution in the vial 22to collect the cells against the filter 29 thereof and thereaftertransfer the cells to the slide 62. Once the cytological specimen hasbeen prepared, the cap 56 is reoriented over the open vial 22 andscrewed onto the body 23 until a substantially fluid-tight seal has beenformed. The axially extending slots 166 which engage the lugs 25 form abi-directional interface, to react against the body lugs 25 during bothremoval and installation of the cap 56 on the body 23. Each of the axialslots 166 may be formed to include, optionally, a generallycircumferentially disposed portion, shown generally at 174, to lock asuitably sized lug against axial translation, if desired.

[0067] Of course, other suitable materials, dimensions, andconfigurations for the body 23, the cap 56, the ribs 35, the lugs 25,the fluid level indicia 31, and other features of the sample vial 22will be apparent to those skilled in the art, those disclosed beingprovided as examples only. For example, while the mating ribs 35 andsectors 146 provide a positive, self-centering drive, other matingstructure such as pins and annular tracks may be used. Further, thesample vial 22 may be used in other applications and contain other thancytological samples in preservative solution.

[0068] The automated specimen preparing system 10 described hereinemploys certain specimen preparing innovations disclosed in theaforementioned patents in combination with batch processing capabilityto prepare gynecological and other cytological specimens in a highlyefficient, reliable manner. The system 10 may also be used to batchprocess other specimens such as those including tissue samples, assayproducts, and other materials. Industry and regulatory acceptance of asystem 10 and method in accordance with the teachings set forth hereinare based, in part, on the capability to maintain one-to-one correlationbetween a patient sample and a specimen produced therefrom. Accordingly,a specimen is not produced on an unmarked slide 62, or on a slide 62 onwhich the specimen indicia are not readable or do not correlate with thesample indicia bar code label 58 identified from the selected vial 22 a.By aborting the specimen preparing cycle prior to collection of thecells against the membrane 29, unidentifiable or misidentified specimenslides are not produced, saving cycle time, consumables, and thepatient's sample.

[0069] When a patient's cells are first collected and deposited in asample vial 22 prefilled with preservative solution, a preprinted barcode label 58 with a unique accession number is applied to the samplevial 22. A second matching bar code label 58 is applied to a patientinformation sheet, listing relevant patient identifying information, aswell as information regarding the tests or analyses to be performed onthe specimen prepared from the sample. Accordingly, when data from thepatient information sheet is entered into a database at a samplereceiving area in a cytological laboratory, data from the bar code label58 on the patient information sheet can also be input, either manuallyor preferably automatically using a laser scanner. The specimen producedfrom the sample with the matching bar code will therefore readily beidentifiable as being from a particular patient.

[0070] Once the system 10 is loaded with the samples and consumables bythe operator, the system 10 runs in an automated manner under control ofthe processor 46 until all sample vials 22 are processed, or until suchtime as a system malfunction occurs or a consumable, such as a samplecollector 28 or slide 62, is depleted. To minimize the likelihood of thelatter situation, sensors are provided throughout the system 10 toverify the presence of sufficient consumables to process all loadedsamples prior to the initiation of automatic operation. Sensors may alsobe provided to monitor levels in the waste bottle 42 and waste bin 44,so that the operator can be alerted to elevated levels of waste, whichcould interrupt processing during automatic cycling.

[0071] Accordingly, when the operator initiates automatic processing,for example, by selecting “Start Batch” from a menu on the display orusing a dedicated keypad input, the system 10 checks that sample vials22 are loaded and a minimum number of necessary consumables and stainingracks are available to complete processing of all the samples. Ifsufficient consumables and waste capacities exist, the system 10 startsthe automatic sample processing cycle. The cycle continues until all ofthe loaded sample vials 22 have been processed, the operator manuallyinterrupts the cycle, or a system error occurs which cannot beautomatically rectified. If insufficient consumables or waste capacitiesexist, the operator may correct the condition or, alternatively,override the system 10 and initiate automatic processing anyway. In theevent a prior automatic cycle had been interrupted, “Start Batch” may beused to resume automatic cycling at the point of interruption, afterchecking system consumables and capacities. In order to protect theoperator from injury by moving components during automatic cycling,access points such as the upper cover 14 may be interlocked.

[0072] If the operator chooses to interrupt the automatic cycle prior tocompletion, the operator may select “Interrupt Batch.” Upon receipt ofthe interrupt signal, the processor 46 interrupts the automatic cycle inan orderly manner, for example, by completing preparation of a specimenin process, transferring the completed specimen slide 62 to a stainingrack 34 in the unloading area 36, and capping and returning the selectedsample vial 22 a to the vial tray 24. After that sample processing cyclehas been completed and moving components are at rest at respective homepositions, the operator access interlocks are unlatched and the operatoris notified. The operator may then open the upper cover 14 or accessother internal areas of the system 10, as desired.

[0073] A “Maintenance” function can also be provided in which the system10 supports operator level maintenance activities such as jogging of themoving components to or from respective home positions to provide theoperator access to various interior volumes of the system 10, forexample, to clear a jam or to retrieve a mishandled slide 62. Othermaintenance functions may include emptying of the waste bottle 42 andbin 44, priming of the fixitive coating station 38 with the fixitivesolution, and advancing of paper in the system printer 48. The system 10may also provide operator selectable diagnostic tests to facilitatesystem troubleshooting or verify proper system operation. For example, apneumatic test may be initiated of the vacuum system 88 of the specimenpreparing apparatus 18 to ensure sufficient volumetric flow rate andnegative pressure level. A display test could be used to verify displayoperation.

[0074] A usage log may be provided to track total number of samplesprocessed, total number of specimens produced, total system run time,and other relevant usage parameters. The processor 46 may also maintainan error log which lists, for example, the last fifty errors detected bythe system 10 and which may be displayed or printed at the discretion ofthe operator. A typical log entry may include date and time of theerror, sample indicia and tray location, and disposition or correctiveaction. In one embodiment, the system 10 identifies any sample vial 22from which a specimen was not successfully prepared, along with thereason for the failure, such as “sample too dense” or “cap too tight.”

[0075] Detectable conditions that could cause specimen quality problemsare flagged by the system 10 and noted to the operator on the displayand paper printout. If possible, a partially collected specimen isreturned to the vial 22 and preparation of the slide 62 is aborted. Ifthe problem is associated with a particular selected sample vial 22 a,the system 10 recovers after returning the selected vial 22 a to thevial tray 24 and recording the error, processing the remaining samplevials 22 in the batch. However, if the error is a system level problem,such as a motor or sensor failure, jammed mechanism, or othermalfunction that is not automatically recoverable and requires operatoror qualified service personnel intervention, the automatic cycle ishalted and the error recorded and reported to the operator.

[0076] Upon installation or commissioning of the system 10, orthereafter as required, the processor 46 may be initialized and setupfunctions enabled or disabled. For example, the date and time may beinput, as well as the respective formats thereof. The system printer 48may be directed to automatically print diagnostic test results or sampleprocessing data at the end of every automatic batch cycle. A date/timestamp may be enabled to print the date and time a specimen was preparedon the frosted end 68 of each slide 62, in addition to the slide indicia82. Optionally, the name or other identifier of the cytologicallaboratory preparing the specimen with the system 10 may be printed onthe slide 62 as well.

[0077] While there have been described herein what are to be consideredexemplary and preferred embodiments of the present invention, othermodifications of the invention will become apparent to those skilled inthe art from the teachings herein. For example, while the system 10 andmethod have been described for preparing a single specimen from eachsample vial 22, the system 10 could be programmed to permit two or morespecimens to be prepared from a single sample vial 22. In suchinstances, the slide indicia 82 could include an additional character oridentifier to indicate the first specimen, second specimen, thirdspecimen, etc. Alternatively, the sample vial 22 could be reprocessed byinserting the vial 22 in a tray 24 in a next batch for a subsequentautomatic cycle.

[0078] The disclosed components of the system 10 may be manufactured invarious sizes, configurations, and materials. Additionally, the system10 may be used to prepare specimens from non-gynecologic cytologicalsamples, such as cells sourced from fine needle aspirates, from mucoidspecimens taken from respiratory and gastrointestinal tracts, from bodyfluids such as serous effusions and urinary and cerebrospinal fluids,from superficial brushings and scrapings from oral cavities, nipplesecretions, skin lesions, and eye brushings, and from other sources.

[0079] The particular methods of manufacture and particular arrangementsof discrete components, geometries, and interconnections therebetweendisclosed herein are exemplary in nature and are not to be consideredlimiting. It is therefore desired to be secured in the appended claimsall such modifications as fall within the spirit and scope of theinvention. Accordingly, what is desired to be secured by Letters Patentis the invention as defined and differentiated in the following claims.

What is claimed is:
 1. A method for processing a specimen from a fluidsample, the method comprising the steps of: (a) identifying indiciacorresponding to the sample; (b) marking an analytical element withindicia corresponding to the sample indicia; (c) reading the elementindicia; (d) verifying the element indicia corresponds to the sampleindicia; and (e) transferring a specimen from the sample to the elementif the element indicia corresponds to the sample indicia.
 2. A methodaccording to claim 1 wherein: the sample comprises particles in a liquidsuspension; and the specimen transferring step utilizes apparatus forcollecting a spatial distribution of the particles from the liquidsuspension and for disposing the collected particles on a stratum of theelement.
 3. A method according to claim 2 wherein the spatialdistribution comprises substantially a monolayer and the stratumcomprises a slide.
 4. A method according to claim 2 wherein thecollecting apparatus comprises a membrane.
 5. A method according toclaim 4 further comprising the step of breaching the membrane after thespecimen transferring step to prevent reuse of the membrane.
 6. A methodaccording to claim 1 wherein the element is marked with ink transferredthereto by a printer.
 7. A method according to claim 6 wherein themarking step comprises a first ink transfer substep at a first locationand a second ink transfer substep at a second location, wherein thesecond location is offset spatially from the first location.
 8. A methodaccording to claim 1 wherein the sample indicia comprises a bar code. 9.A method according to claim 8 wherein the sample indicia identifyingstep utilizes a bar code scanner.
 10. A method according to claim 1wherein the element indicia comprises an alphanumeric character.
 11. Amethod according to claim 10 wherein the element indicia reading steputilizes an optical character recognition system.
 12. An apparatus forprocessing a specimen from a fluid sample comprising: a processor; anidentifier in communication with the processor for identifying indiciacorresponding to the sample; a marker in communication with theprocessor for marking an analytical element with indicia correspondingto the sample indicia; a reader in communication with the processor forreading the element indicia, wherein the processor verifies whether theelement indicia corresponds to the sample indicia; and a specimentransferrer in communication with the processor for transferring aspecimen from the sample to the element if the element indiciacorresponds to the sample indicia.
 13. An apparatus according to claim12 wherein: the sample comprises particles in a liquid suspension; andthe specimen transferrer collects a spatial distribution of theparticles from the liquid suspension and disposes the collectedparticles on a stratum of the element.
 14. An apparatus according toclaim 13 wherein the spatial distribution comprises substantially amonolayer and the stratum comprises a slide.
 15. An apparatus accordingto claim 13 wherein the specimen transferrer comprises: a membrane forcollecting the spatial distribution; and means for breaching themembrane to prevent reuse of the membrane after the collected particlesare disposed on the stratum.
 16. An apparatus according to claim 12wherein the marker comprises an ink printer.
 17. An apparatus accordingto claim 16 wherein the marker first transfers ink to the element at afirst location and then transfers ink to the element at a secondlocation, wherein the second location is offset spatially from the firstlocation.
 18. An apparatus according to claim 12 wherein the sampleindicia comprises a bar code.
 19. An apparatus according to claim 18wherein the identifier comprises a bar code scanner.
 20. An apparatusaccording to claim 12 wherein the element indicia comprises analphanumeric character.
 21. An apparatus according to claim 20 whereinthe reader comprises an optical character recognition system.